Structure-based drug design for hypoxia-inducible factor prolyl-hydroxylase inhibitors and its therapeutic potential for the treatment of erythropoiesis-stimulating agent-resistant anemia: raising expectations for exploratory clinical trials

Abstract

Introduction: Anemia occurs in various chronic diseases and its treatment is dramatically improved after the appearance of erythropoiesis-stimulating agents (ESA). However, there are several problems regarding the use of ESA including: i) invasiveness, ii) high cost and iii) ESA resistance. Therefore, there is a need to develop small molecule drugs which can improve these problems. Hypoxia-inducible factor (HIF) plays a key role in regulating erythropoietin production. HIF stabilizers, particularly, prolyl hydroxylase domain-containing protein (PHD) inhibitors, have emerged as small molecule-based anti-anemia medicine.Areas covered: This article discusses the current status of PHD inhibitors and the pros and cons of currently tested methods. Specifically, the article reviews the advantages of structure-based drug design in the development of PHD inhibitors and looks at future perspectives within the field.Expert opinion: Despite the fact that structure-based drug design has dramatically improved drug discovery, testing on humans is still one of the most time-consuming parts of drug discovery and one that is not accelerated by structural approaches. Exploratory clinical trials, first-in-man studies have emerged as a new strategy for preclinical and clinical development of drugs. Exploratory clinical trials will not only reduce the time and cost in preclinical trials but also provide important information on candidate drug's pharmacological effects in humans. Exploratory clinical trials may be a potential alternative strategy for the drug discovery in the future.